JPH11209330A - Continuous production of diazomethane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing diazomethane in a high yield rapidly and continuously without danger of explosion and without influence of a harmful substance on operators. SOLUTION: N-Methyl-N-nitrosoamine is dissolved in a mixed solution of an organic solvent having water compatibility to dissolve N-methyl-N- nitrosoamine and an organic solvent having water incompatibility to dissolve diazomethane. The flow of the mixed solution is mixed with that of an aqueous solution of an inorganic salt. After a proper retention time, the mixture is separated into an aqueous phase and an organic phase and both the phases are separated. A series of processes of these operations are continuously carried out. In the case in which N-methyl-N-nitrosourea is used as the amine, before the diazomethane process, an aqueous solution of methylurea and a nitrite is mixed with an organic solution of an inorganic acid or an organic acid in which the solvents of the organic solution are the above-mentioned two organic solvents. After a proper retention time, the solution is separated into an aqueous phase and an organic phase to cause the phase separation of both the phases. A series of processes of these operations are continuously performed. The obtained organic phase is successively supplied to a diazomethane process step.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for synthesizing diazomethane.

Diazomethane (CH ₂ ＮN ＝ N, also known as azimethylene or diazirine) is widely used in chemical synthesis. One of its uses is carboxylic acids, phenols, alcohols,
Examples of the use of enols and heteroatoms such as nitrogen and sulfur as methylating agents. Other uses include ring expansion or chain extension of ketones and conversion of ketones to epoxides. Yet another example is the use of acid chlorides by themselves as a useful intermediate, α
-Examples used to convert to diazoketones.
Yet another use is for use in cycloaddition reactions with olefins to make cyclopropyl rings or nitrogen-containing heterocyclic rings. Still other examples include those used to produce viral protease inhibitors, including those used to combat HIV. A particularly important class of viral protease inhibitors is the amino acid isotope (isos) produced by adding a functionalized carbon to an amino acid having two carbon atoms.
teres). For example, the inhibitor SAQUINAVIR
® (Roche Laboratories) is manufactured in this manner. For the conversion to be successful, the carbon addition reaction must be carried out without compromising the chirality of the amino acid or affecting any remaining portion of the amino acid molecule. Diazomethane satisfies these requirements in a modified Alund-Eisert reaction.

[0003]

A limiting factor in the use of diazomethane is its dangerous nature. Diazomethane is a carcinogen, a potent allergen, and toxic. Moreover, diazomethane is explosive. For this reason, the technical literature on the synthesis of diazomethane takes care not to use polished joints and glassware without fire finish, and no synthesis other than laboratory bench-scale synthesis has been reported. Not. Equipment specially designed for diazomethane production,
For example, A in Milwaukee, Wisconsin, USA
The DIAZALD® instrument from ldrich Chemical Company, Inc. can process up to 300 mmoles in a single batch reaction.
It is designed to obtain le (mmol) of diazomethane. Black, TH's paper `` The Preparation and
Reactions of Diazomethane ", Aldrichimica Acta, 1
6 (1), pages 3-10 (1983). Manufacturing, referred to as "large scale," is described in U.S. Pat. No. 5,459,243, issued Oct. 17, 1995, "Apparatus an.
d Processes for the Large Scale Generation and Tra
Acevedo et al. in "nsfer of Diazomethane". However, the reactions disclosed in that patent are 10
Performed on a laboratory Erlenmeyer glassware on a scale of 0 mmole (4.2 g).

[0004] These constraints limit the cost-effectiveness of diazomethane production and the use of diazomethane. In order to take full advantage of the versatility of this compound, there is a need for new manufacturing methods with improved yields and production rates without increasing the risk of injury to factory technicians.

Accordingly, an object of the present invention is to provide a method for producing diazomethane without a risk of explosion, without the effects of harmful substances on workers, and with a good production yield and production rate. .

[0006]

SUMMARY OF THE INVENTION The inventors have now discovered that diazomethane can be produced in a continuous production process with little or no risk of explosion. First, N-methyl-N-nitrosamine is dissolved in a mixture of two organic solvents. One of the solvents is at least partially water-miscible and dissolves N-methyl-N-nitrosamine, and the other solvent is substantially less water-miscible than the former solvent and has a separate phase for water. To dissolve the diazomethane. The stream of the above solution is mixed with the stream of the aqueous solution of the inorganic base, and after an appropriate residence time, the aqueous phase (aqueous phase)
A series of processes of sedimentation of the organic phase and separation of the two phases are performed on a continuous basis, and diazomethane is recovered as an organic solution. All stages of this manufacturing process are in the liquid phase, by limiting its temperature below 15 ° C.
Do. This reduces or eliminates the risk of explosion, since the production of diazomethane vapors is avoided and the headspace used is minimized.
Moreover, diazomethane can be produced in high yield.

In a second aspect of the invention, N-methyl-N-nitrosourea is used as the N-methyl-N-nitrosamine, which is produced on site as part of the continuous production method of the invention. An aqueous solution of methyl urea and nitrite ions is mixed with an organic solution of a mineral acid (inorganic acid) or an organic acid, wherein the solvent in the organic solution is a mixture of the organic solvents described in the preceding paragraph, On a continuous basis, the aqueous and organic phases are allowed to settle after a suitable residence time, causing phase separation. The organic phase, which is a solution of N-methyl-N-nitrosourea in an organic solvent, is then mixed with the aqueous inorganic base solution, all on a continuous basis and at low temperature, as described in the preceding paragraph, and the new organic phase is added. The aqueous phase is allowed to settle after a suitable residence time, the phases are separated, and the diazomethane is recovered as an essentially dry organic solution.

[0008] An advantage of such a continuous production method is that it is not necessary to simultaneously distill a large amount of an organic solvent such as ether and diazomethane. The various steps of the above process are performed entirely in the liquid phase to significantly reduce or eliminate the risk of explosion. The process of the present invention further provides the benefits of a continuous process as a whole, reduces waste by utilizing recycle streams, and reduces temperature, concentration,
Reaction times and other process parameters can be controlled over a wider range. Further features, embodiments and advantages of the present invention will become apparent from the following description.

[0009]

DETAILED DESCRIPTION OF THE INVENTION The N-methyl-N-nitrosamine used in the process of the present invention is an N-methyl-N-nitrosamine which reacts with an inorganic base at a low temperature at which the process of the present invention is carried out. is there. Specific examples of the N-methyl-N-nitrosamines include compounds represented by the following chemical formula [Formula 5].

[0010]

Embedded image In the formula, R is any one of the following [Chemical Formula 6], [Chemical Formula 7] or [Chemical Formula 8],

[0011]

Embedded image

[0012]

Embedded image

[0013]

Embedded image Here, the symbol R ¹ represents H, lower alkyl or nitro (—NO ₂ —), and R ² represents H or lower alkyl. The term "lower alkyl" in this specification is used in its ordinary sense and generally refers to branched and unbranched alkyl groups, having up to 4 carbon atoms and preferably being saturated. including. Preferred alkyl groups present are unbranched alkyl groups, more preferably methyl or ethyl,
And most preferably methyl. Examples of N-methyl-N-nitrosoureas useful in the present invention include N-methyl-N-nitrosourea, N, N'-dimethyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosourea. Urea, N-methyl-N-nitrosoguanidine, N, N'-
Dimethyl-N-nitrosoguanidine, N-methyl-N '
-Nitro-N-nitrosoguanidine, N-methyl-N-
Nitrosocarbamic acid, methyl N-methyl-N-nitrosocarbamate and ethyl N-methyl-N-nitrosocarbamate.

The first organic solvent is at least partially miscible with water, preferably having a solubility of at least about 50 parts by weight per 100 parts by weight of water, and more preferably having a solubility of 100 parts by weight of water. At least about 100 parts by weight solvent per part, and most preferably a miscible solvent in any proportion. Examples are tetrahydrofuran and methyl t-butyl ether. Tetrahydrofuran is preferred.

A second organic solvent is a solvent that dissolves diazomethane as it forms and extracts the diazomethane from the aqueous phase into a separate organic phase, the boiling point of which is higher than the process temperature. The solvent need not be completely miscible with water, and solvents that form a separate phase and extract most, if not all, the diazomethane can be used. With this in mind, the term "water-immiscible (non-water-miscible)" is used herein for convenience. The solubility of the second solvent in water is substantially lower than the first solvent. In this context, the term "substantially small" means that, in the relative amounts used, the first organic solvent does not form a separate layer with water, while the second solvent forms a separate layer. Means to do. The difference in miscibility with water is generally
At least about 30 parts by weight per 00 parts by weight, preferably at least about 50 parts by weight per 100 parts by weight of water, and most preferably at least about 100 parts by weight per 100 parts by weight of water. Preferred organic solvents are vapor spaces in the reaction system containing the evaporated diazomethane,
Solvents having a vapor pressure high enough to also contain a sufficient proportion of solvent vapor to reduce the risk of explosion. Thus, preferred solvents are those having a boiling point in the range of about 15C to about 40C. Examples of suitable solvents are diethyl ether, methyl ethyl ether and methyl propyl ether. Most preferred is diethyl ether.

The relative amount of tetrahydrofuran and non-water miscible organic solvent in the flowing fluid is not critical to the present invention and may vary. The amount of tetrahydrofuran used is sufficient to dissolve the reactants such that the reaction rate is fast enough to complete the reaction with an economically reasonable residence time. A contributing factor is the mixing efficiency of the reactor, with higher efficiency mixers, such as high pressure static mixers or high shear mixers, which can reduce the amount of tetrahydrofuran used. Similarly, the amount of the organic solvent immiscible with water may be any amount as long as it can extract all the diazomethane produced by the reaction. A factor contributing to this point is the flow rate of the reactants passing through the continuous flow system. As the time required to cause phase separation is shortened, more water-immiscible organic solvents are required. As noted above, it is further preferred to use sufficient organic solvent so that the vapor phase above the liquid reaction medium is sufficiently diluted with the evaporating solvent such that there is no risk of explosion. In most cases, from a functional and economic point of view, the best result is that the molar ratio of the two solvents is from about 0.3: 1 to about 3: 1, preferably about 0.5:
It is achieved by being in the range of from about 1 to about 2: 1, and most preferably from about 0.75: 1 to about 1.33: 1.

The concentration of N-methyl-N-nitrosamine can be varied, and the main consideration is that the water-immiscible organic solvent should be concentrated so that the concentration of the vapor phase is lower than within the explosion range. Maintaining a sufficiently low concentration. In a preferred embodiment of the process of the present invention, the N-methyl-N-nitrosamine and the non-water-miscible organic solvent have a molar ratio of about 0.02: 1 to about 0.25:
1 (amine: solvent), most preferably about 0.10: 1
Use at about 0.15: 1.

The choice of the inorganic base is not critical for this invention, but the preferred inorganic base is potassium hydroxide. This base is supplied in a stoichiometric excess relative to N-methyl-N-nitrosamine in order to completely convert the N-methyl-N-nitrosamine. The preferred molar ratio of base to amine is at least about 1.5: 1, and more preferably about 1.5: 1, especially when using potassium hydroxide as the base and N-methyl-N-nitrosourea as the amine. : 1 to about 50: 1, and most preferably from about 1.8: 1 to about 20: 1.

The temperature at the reaction stage of the production method of the present invention is as follows:
Maintained at about 15 ° C. or lower, preferably from about −10 ° C. to about +1
Maintain in the range of 5 ° C, most preferably from about -5 ° C to about +
Maintain within 5 ° C. The resulting aqueous and organic phases are also
It is maintained within these temperature ranges during the settling and separation of both phases and all transfers between the various stages. The residence time of the stream in the reaction steps required to complete the reaction before phase separation can vary with other parameters of the process, such as concentration and temperature. Generally, about 5 minutes
Best results are obtained with a residence time in the range of 1 hour. Further, it is preferable to stir the reaction mixture.

Once the phases have separated, the aqueous phase is a waste stream containing no N-methyl-N-nitrosourea or diazomethane, but mainly containing the inorganic base cyanate. This cyanate is potassium cyanate when the base used is potassium hydroxide, but is easily converted to its acid form when an acid is added, and the acid form is easily decomposed. Thus, for example, treatment with hydrochloric acid converts potassium cyanate in the vapor waste stream to an acid, which decomposes to ammonia and carbon dioxide, leaving a waste stream containing only potassium chloride and ammonium chloride. .

The organic phase comprises diazomethane dissolved in tetrahydrofuran and a water-immiscible solvent (preferably
Diethyl ether). This stream can be washed with water or concentrated alkali to remove any residual impurities. Washing with a load alkali is preferred. This is because the charged alkali removes any residual moisture, leaving a stream of anhydrous (less than 0.1% moisture) diazomethane. The anhydrous diazomethane can be prepared in an organic solvent at a concentration ranging from about 2% to about 10% by weight. A preferred aqueous chargeable alkali stream is 45-50% KOH, which can be recycled to the reaction stage where diazomethane is formed. The stream of anhydrous diazomethane remaining after washing with chargeable alkali can be fed directly to a batch reactor using diazomethane in the next reaction, or can be mixed with one or more other flowing streams in a continuous reaction. it can. In the case of a batch reaction, the flowing diazomethane stream is alternately sent to one of the two reactors, where the reaction is performed in one of the reactors and the product is recovered (inspection) in the other. be able to.

Continuous settling and phase separation can be achieved in conventional plant equipment and the time required for complete separation, ie, in the phase separator until the organic phase is removed as a separate stream. The allowable residence time depends on the degree of stirring and the arrangement of the phase separator. However, in general,
Suitable separation is from about 3 seconds to about 1 minute, preferably about 10 minutes.
Achieved with a residence time in the separator of from seconds to about 30 seconds. Separation is easily achieved without the aid of surfactants. Separation and residence time can be monitored and controlled by ultrasonic level detection or other known level detection means.

In a second aspect of the invention, the production steps detailed above comprise a series of steps in which N-methyl-N-nitrosourea is produced on a continuous basis by nitrosating N-methylurea. (Downstream). The reaction step of this nitrosated portion of the production process is carried out by continuously contacting an aqueous solution of methyl urea, aqueous nitrous acid ions, and an organic solution of an acid with the same organic solvent mixture used in the diazomethane production portion. Will be

The nitrite ion (NO ₂ ⁻ ) is supplied in the form of nitrite and is converted to nitrite (HNO ₂ ) by an acid, which is used for the nitrosation of N-methylurea. It is a species that performs nitrosation. Any nitrite that can be converted to nitrite in this way can be used. A preferred example is sodium nitrite,
Other nitrites can be used as well. Generally, the salts can be converted to the acids with mineral acids (inorganic acids) and organic acids. Mineral acids are preferred, especially hydrochloric acid and nitric acid. If a stainless steel reactor is used, nitric acid is preferred over hydrochloric acid. The acid is preferably used in a stoichiometric excess relative to the nitrite, but the relative amounts are not critical. A typical feed is about 10%
It contains from about a 50% molar excess of acid. Nitrite ions are likewise preferably used in molar excess relative to N-methylurea, but this amount is not too severe. The percent excess of nitrite ion to N-methylurea used for best results is typically in the range of about 3% to about 30%.

The concentration of each of these substances in the aqueous and organic solvents may also vary. Considerations in selecting an appropriate concentration are mainly due to safety considerations in connection with the reaction of diazomethane as described above, the intermediate of N-methyl-N-nitrosourea in the organic phase. It is to control the concentration. Also, by selecting an appropriate concentration, it is possible to control the reaction rate and thus the temperature in the reaction stage. But,
Generally, these concentrations are not critical. In most cases, for example, (aqueous) N-methylurea at a concentration of about 1 M to about 10 M, (aqueous) nitrite at a concentration of about 1 M to about 10 M, and a volume ratio of organic solvent to aqueous phase of about 1.3.
The reactants can be used most efficiently with an organic solvent of from about 10.0 to about 10.0 (organic: aqueous), preferably about 1.5 to about 5.0. The amount of acid in the organic feed may be as described above,
It can be determined from the preferred ratio of the amount of acid to the amount of nitrite.

The temperature of the reaction step for performing the nitrosation reaction is as follows:
It is not critical to the invention and may vary. In most cases, best results are obtained at a temperature in the range of about 5C to about 30C, preferably in the range of about 10C to about 20C. The reaction residence time (ie, the aqueous and organic phases
The time of contact before transfer to the phase separator) is N-
Any amount of time is sufficient to completely convert methyl urea to N-methyl-N-nitrosourea, which can vary with process parameters such as concentration and temperature. In most cases, the residence time is at least about 5 minutes, and if process parameters are used within the above ranges,
Typical residence times range from about 5 minutes to about 60 minutes with stirring.
Minutes. If agitation is used at all stages of the manufacturing process, the agitation speed of about 260 rpm to about 300 rpm provides for proper phase contact.

In both the nitrosation reaction and the diazomethane reaction, the flow vessel in which each reaction is performed may be a pipe of a certain length, or a tank having an inlet port and an outlet port. When using a pipe of a certain length, a static mixer arranged inside the pipe performs the function of stirring, while in the case of a tank, it can be stirred by a mechanical stirrer. In the case of tanks, rather than a single tank, a cascade (cascade) of two or more series of tanks can be used to better control temperature and residence time. The right choice will be apparent to the skilled plant design engineer.As with the diazomethane portion during the manufacturing process, the continuous sedimentation and phase separation following the nitrosation reaction is performed by conventional plant equipment. And the length of time required to achieve complete separation depends on the degree of agitation and the configuration of the phase separator. However, in general, a suitable separation is from about 3 seconds to about 1 minute, preferably from about 10 seconds to 20 minutes.
Achieved with a separator residence time of seconds. Separation is easily achieved without the aid of surfactants. The separation and dwell time can be monitored and controlled by ultrasonic level detection or other known means of level detection.

[0028]

FIG. 1 shows an embodiment of a process flow of a laboratory scale model for implementing the manufacturing method of the present invention. The composition and temperature of each numbered flow in this flow chart are shown in the following tables [Table 1], [Table 2], and [Table 3].

[0029]

[Table 1]

[0030]

[Table 2]

[0031]

[Table 3] In the flow chart of FIG. 1, vessels 1 and 2 are flow-reaction vessels, each equipped with a stirrer, vessel 1 shows a first-stage reaction of a two-stage nitrosation reaction, and vessel 2 shows a first-stage reaction. Shows a two-step reaction. The following three flows are sent to the container 1. That is, methyl urea 1 dissolved in water
1. Sodium nitrite 12 dissolved in water, and 70
% Aqueous nitric acid, tetrahydrofuran and diethyl ether 13. The residence time in the container 1 is the temperature 1
At 2 ° C. ± 3 ° C., 10.0 minutes. Intermediate stream 14 transports the product from vessel 1 to vessel 2 and the residence time in vessel 2 is the same temperature for an additional 10.0 minutes. The fully nitrosated product 15 is then transported to the phase separator 3, where the residence time is between 5.0 and 1
0.0 minutes and the temperature is 20 ° C. ± 10 ° C.
Is maintained. The organic phase 16 containing N-methyl-N-nitrosourea and the aqueous phase 17 are released separately. The aqueous phase 17 is led to a waste liquid treatment vessel 14, to which a charged alkaline aqueous solution 18 is added to obtain a treated aqueous waste liquid stream 19.

The organic phase 16 comprises a two-stage flow reactor 5,
6, the organic phase is brought into contact with an aqueous solution of potassium hydroxide. The residence time in the two vessels 5, 6 is 6.7 minutes each, and each vessel is maintained at a temperature of 0 ° C. ± 5 ° C. The two-phase product stream 22 is sent to the phase separator 7 where the residence time is 4.5 minutes and the temperature is -10.
It is maintained at +/- 5 ° C. The separated organic phase 23 contains diazomethane dissolved in ether and tetrahydrofuran, and the aqueous phase 24 is led to an aqueous waste treatment vessel 8, to which nitric acid 25 is added and a second treated aqueous A waste stream 26 is obtained.

[0033]

As described above, the method for producing diazomethane according to the present invention starts from a solution of raw material chemical substances and is carried out by a process of contacting, reacting, and phase-separating them. A series of plants can be constructed by connecting and arranging in a cascade.Thus, while the reactants flow through each device and the connecting pipe, the target product is continuously produced under safe control. There is no danger of explosion and there is no harmful substance effect on workers, and large quantities of diazomethane can be produced in high yield.

[0034]

[Supplement] The above is mainly provided for the purpose of illustration. Operating conditions of the process described in this specification,
Those skilled in the art will readily appreciate that the raw materials, ratios and procedural steps, and other parameters, can be further modified or substituted in various ways without departing from the spirit and scope of the invention. Will.

[Brief description of the drawings]

FIG. 1 is a flow chart of a manufacturing process illustrating an embodiment of the present invention.

[Explanation of symbols]

1 ... container of the first stage of nitrosation reaction, 2 ... container of the second stage of nitrosation reaction, 3, 7 ... phase separator, 4, 8 ...
Waste liquid treatment vessel, 5… Container for the first stage of diazomethane production,
6: container for the second stage of diazomethane formation, 11: methyl urea dissolved in water, 12: sodium nitrite dissolved in water, 13 ... 70% aqueous nitric acid, tetrahydrofuran and diethyl ether, 14 ... intermediate stream, 15 ... nitroso , Organic phase, 17, 24 ... aqueous phase, 18 ... aqueous alkali solution, 19, 26 ... treated aqueous waste stream, 20 ... potassium hydroxide aqueous solution, 22 ... two-phase product stream , 25 ... nitric acid.

Continuation of front page (72) James C. Inventor. Bernard United States of America 95682 California Single Springs Holly Drive 4440 (72) Inventor Harlan EF. Rees United States 95667 Placerville, Rose Lane, California 1954

Claims (10)

[Claims] 1. A process for the continuous production of diazomethane, comprising: (a) (i) a first organic solvent which is at least partially miscible with water and dissolves N-methyl-N-nitrosamine; An organic solution containing N-methyl-N-nitrosamine dissolved in a mixture with a second organic solvent that is substantially less miscible with water than the solvent of (Ii) continuously contacting with an aqueous solution of an inorganic base, wherein the N-methyl-N-nitrosamine has the following formula [Chemical Formula 1], In the formula, R is a compound represented by the following formulas [Chemical formula 2], [Chemical formula 3] and [Chemical formula 4]
A member selected from the group consisting of: Embedded image Embedded image R ¹ is a member selected from the group consisting of H, lower alkyl and nitro; and R ² is H
And a member selected from the group consisting of lower alkyl, wherein said contacting is performed in such a way that said inorganic base is in stoichiometric excess relative to said N-methyl-N-nitrosamine. Flow rate, about -10 ° C to about + 15 ° C
At a temperature of and for a contact time of at least about 5 minutes to produce a mixture of products, (b) separating the mixture of products from (i) the N-methyl-N-nitrosamine with the inorganic base The organic phase containing diazomethane formed by the reaction of (a) and the aqueous phase (ii) are combined with each other by about -1.
Continuously settling while maintaining the temperature between 0 ° C. and about + 15 ° C., and then (c) continuously separating the organic phase from the aqueous phase. 2. The method according to claim 1, wherein the first organic solvent is tetrahydrofuran. 3. The method according to claim 1, wherein the second organic solvent is a member selected from the group consisting of diethyl ether, methyl ethyl ether and methyl propyl ether. . 4. The method of claim 1, wherein said N-methyl-N-nitrosamine and said second organic solvent are present in said organic solution in a concentration of about 0.02: 1 to about 0.2.
A method characterized in that it is present in a 5: 1 molar ratio. 5. The method according to claim 1, wherein the relative flow rate in (a) is such that the inorganic base is the N-
At least about 1. 1 to methyl-N-nitrosamine.
A method wherein the relative flow rates are such that they are delivered in a 5: 1 molar ratio. 6. A process for continuously producing diazomethane, comprising: (a) (i) an aqueous solution of methyl urea, (ii) an aqueous solution of nitrite ion, and (iii) at least partially miscible with water. Yes and N
Contacting an organic solution of an acid with a mixture of a first organic solvent that dissolves -methyl-N-nitrosourea and a second organic solvent that forms a separate phase when contacted with water; A substantial portion of the methyl urea is N-methyl-N-
Producing a first product mixture that has been converted to nitrosourea; and (b) combining the first product mixture with (i) a first organic phase containing the N-methyl-N-nitrosourea. (Ii) continuously settling with the first aqueous phase, (c)
The first organic phase is continuously separated from the first aqueous phase, and (d) separating the first organic phase separated as described above with an aqueous solution of an inorganic base and the inorganic base with the N 2 Continuous contact at a relative flow rate that is in stoichiometric excess with respect to -methyl-N-nitrosourea, at a temperature of about -10 ° C to about + 15 ° C, and for a contact time of at least about 5 minutes. (E) containing the diazomethane formed in the reaction of the N-methyl-N-nitrosourea with the inorganic base from the N-methyl-N-nitrosourea. The second organic phase and (ii) a second aqueous phase, allowing the second organic phase and the second aqueous phase to settle while maintaining the temperature at about -10 ° C to about + 15 ° C; (F) continuously separating the second organic phase from the second aqueous phase. How to be. 7. The method according to claim 6, wherein said aqueous solution of nitrite ions is an aqueous solution of sodium nitrite and said acid is a member selected from the group consisting of hydrochloric acid and nitric acid. Features method. 8. The method of claim 6, wherein (a) the nitrite ion and the acid are both used in stoichiometric excess with respect to the methyl urea. Features method. 9. The method according to claim 6, wherein said first organic solvent is tetrahydrofuran, and said second organic solvent is selected from the group consisting of diethyl ether, methyl ethyl ether and methyl propyl ether. The method characterized by being a member to be performed. 10. The method of claim 6, wherein the temperature in (d) and the temperature in (e) are both about -5 ° C to about + 5 ° C.